Abstract
Creutzfeldt-Jakob disease (CJD) is the most frequent human Prion-related disorder (PrD). The detection of 14-3-3 protein in the cerebrospinal fluid (CSF) is used as a molecular diagnostic criterion for patients clinically compatible with CJD. However, there is a pressing need for the identification of new reliable disease biomarkers. The pathological mechanisms leading to accumulation of 14-3-3 protein in CSF are not fully understood, however neuronal loss followed by cell lysis is assumed to cause the increase in 14-3-3 levels, which also occurs in conditions such as brain ischemia. Here we investigated the relation between the levels of 14-3-3 protein, Lactate dehydrogenase (LDH) activity and expression of the prion protein (PrP) in CSF of sporadic and familial CJD cases. Unexpectedly, we found normal levels of LDH activity in CJD cases with moderate levels of 14-3-3 protein. Increased LDH activity was only observed in a percentage of the CSF samples that also exhibited high 14-3-3 levels. Analysis of the PrP expression pattern in CSF revealed a reduction in PrP levels in all CJD cases, as well as marked changes in its glycosylation pattern. PrP present in CSF of CJD cases was sensitive to proteases. The alterations in PrP expression observed in CJD cases were not detected in other pathologies affecting the nervous system, including cases of dementia and tropical spastic paraparesis/HTLV-1 associated myelopathy (HAM/TSP). Time course analysis in several CJD patients revealed that 14-3-3 levels in CSF are dynamic and show a high degree of variability during the end stage of the disease. Post-mortem analysis of brain tissue also indicated that 14-3-3 protein is upregulated in neuronal cells, suggesting that its expression is modulated during the course of the disease. These results suggest that a combined analysis of 14-3-3 and PrP expression pattern in CSF is a reliable biomarker to confirm the clinical diagnosis of CJD patients and follow disease progression.
Highlights
Protein misfolding is a common hallmark of several neurodegenerative disorders including Alzheimer’s disease, Parkinson’s disease, amyotrophic lateral sclerosis (ALS), as well as Prionrelated disorders (PrDs), among other pathologies [1]
This work was performed as part of a coordinated effort to develop a centralized diagnosis and surveillance of Chilean patients suffering from a prevalent human PrD form
We monitored the levels of 14-3-3 protein, Lactate dehydrogenase (LDH) activity and different aspects of prion protein (PrP) biology in the cerebrospinal fluid (CSF) of patients with the clinical diagnosis of CreutzfeldtJakob disease (CJD)
Summary
Protein misfolding is a common hallmark of several neurodegenerative disorders including Alzheimer’s disease, Parkinson’s disease, amyotrophic lateral sclerosis (ALS), as well as Prionrelated disorders (PrDs), among other pathologies [1]. An elevation of 14-3-3 levels in the CSF is thought to occur because of non-specific release from areas after massive brain damage, which accompanies a variety of neurological conditions including central nervous system infections and inflammatory diseases, brain tumors, and other types of neurodegenerative diseases [20]. These studies reflect the need for additional biomarkers for diagnosis and to follow disease progression in CJD, which represents a general need for most neurodegenerative diseases. Our data suggest that monitoring the pattern and levels of PrPC in combination with measurements of 14-3-3 level in CSF of CJD patients may be used as a predictive biomarker for CJD diagnosis and progression
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